Epidemic viral infections are responsible for significant worldwide loss of life and income in human illnesses ranging from the common cold to life-threatening influenza, West Nile and HIV infections. Timely detection, diagnosis and treatment are key in limiting spread of disease in epidemic, pandemic and epizootic settings. In particular, prophylactic and therapeutic agents that rapidly inhibit viral assembly and propagation are particularly useful in treatment regimens.
Influenza virus of type A (IAV) causes acute respiratory infections that are highly contagious and afflict humans and animals with significant morbidity and mortality. Thus, there is a need in the clinical arts for new and improved anti-viral medicinal agents. This invention meets these needs.
Activation of host innate immune system aims at controlling the spreading and deleterious effects of IAV infection. However, excessive inflammatory response, due to a dysregulation of cytokine release and strong recruitment of neutrophils at the site of infection, may also mediate severe lung inflammation and increased pathogenesis of IAV. Cytokine dysregulation during IAV infection is thus often associated with fatal outcome of IAV.
The sites of virus replication in the respiratory tract represent complex microenvironments, in which extracellular proteases are present in large amounts. Some of these proteases (trypsin, tryptase) can play a role both in virus replication (Riteau B. et al. 2006; LeBouder F. et al. 2008) and innate immune responses as they are important mediators of inflammatory processes through the activation of a family of receptors called Protease-Activated Receptors (PARs) (Steinhoff M. et al. 2005; Vergnolle N. et al. 2008).
To date four PARs, activated by different proteases, have been cloned (PAR1-4). After cleavage of the receptor by proteases, the newly released amino-terminal sequence binds and activates internally the receptor.
The role of PAR1 in lung IAV infection has never been documented. However elevated PAR levels of pAR1 have been observed in the airways of IAV-infected mice (Lan R S. et al. 2004), suggesting a role for this receptor in the pathogenesis of viral disease. The specific role for PAR1 activation/inactivation in vivo or in vitro has never been addressed.